Type 2 immune polarization is associated with cardiopulmonary disease in preterm infants.
Jason C LaoChristine B BuiMerrin A PangSteven X ChoIna RudloffKirstin ElgassJan SchroederAnton MaksimenkoNiamh E ManganMalcolm Ronald StarkeyElisabeth M SkuzaYu Bo Yang SunFriederike BekerClare L CollinsCamille Omar Farouk KamlinKai KönigAtul MalhotraKenneth TanChristiane ThedaMorag J YoungCatriona A McleanNicholas J WilsonArvind SehgalPhilip Michael HansbroJames T PearsonMohammad Mahfuz ChowdhuryAlex VeldmanPhilip J BergerClaudia A Nold-PetryMarcel F NoldPublished in: Science translational medicine (2022)
Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood samples collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3 + CD4 + T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1β and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.
Keyphrases
- preterm infants
- single cell
- pulmonary hypertension
- low birth weight
- oxidative stress
- flow cytometry
- end stage renal disease
- healthcare
- gene expression
- cell proliferation
- newly diagnosed
- type diabetes
- cardiovascular disease
- chronic kidney disease
- coronary artery
- prognostic factors
- high throughput
- pregnant women
- immune response
- stem cells
- pulmonary arterial hypertension
- weight loss
- physical activity
- risk factors
- peritoneal dialysis
- cardiovascular events
- toll like receptor